This project will focus on gene expression profiles in the systemic form of Juvenile Rheumatoid Arthritis. Specific Aim 1 will focus on the gene expression profiles that will distinguish patients with systemic JRA from other clinical forms of the disease, and identify patients bound to develop progressive erosive arthritis at later stages of the disease. Specific Aims 2 and 3 will focus on Macrophage Activation Syndrome and its relationship to clinically similar familial hemophagocytic lymphohistiocytosis (FHLH). MAS is a well recognized life-threatening complication of soJRA. As in FHLH, its development is associated with uncontrolled expansion of T-cells and macrophages. The pathogenesis of FHLH has recently been associated with decreased natural killer (NK) and cytotoxic cell functions secondary to mutations in the gene encoding perforin. All MAS patients included on our preliminary studies had profoundly depressed NK function suggesting that this abnormality is likely to be central to the development of MAS as well. Moreover, patterns of perforin expression in some of the MAS patients were similar to those in FHLH carries. Therefore, in Specific Aim 2 we will assess the extent of NK dysfunction in soJRA and identify gene expression profiles associated with this particular immunologic abnormality. Specific Aim 3 will focus on the changes in the gene expression profiles specific to the acute phase of MAS and FHLH themselves rather than the underlying immunologic abnormalities. We expect that the comparison of the obtained expression profiles should clarify the relationship between MAS and HLH, a better understood disease with a known genetic defect. The long-term goal of this proposal to define the pattems of immune gene dysregulation which leads to the development of soJRA and MAS.